Thiadiazole derivatives

ABSTRACT

3,7-disubstituted-3-cephem-4-carboxylic acid compounds having bacteriostatic properties and the following formula: ##STR1## in which R 1  is thiadiazolyl or isothiazolyl, each of which may have suitable substituent(s), or thiazolyl; R 2  is hydrogen or lower alkyl; R 3  is carboxy or protected carboxy; R 4  is hydrogen, acyloxy or a heterocyclicthio group which may have suitable substituent(s); and R 5  is hydrogen or lower alkoxy, process for making same and treating infectious diseases therewith.

This is a division, of application Ser. No. 206,299, filed Nov. 12,1980, now U.S. Pat. No. 4,350,693, which in turn was a division of Ser.No. 26,779, filed Apr. 3, 1979, now U.S. Pat. No. 4,263,291, which inturn was a continuation-in-part of Ser. No. 839,974, filed Oct. 6, 1977,now abandoned.

The present invention relates to new3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof. More particularly, it relatesto new 3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof which have antimicrobialactivites and to processes for the preparation thereof, topharmaceutical composition comprising the same, and to a method of usingthe same therapeutically for treatment of infectious diseases in humanbeing and animals.

Accordingly, it is one object of the present invention to provide3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof, which are highly activeagainst a number of pathogenic microorganisms.

Another object of the present invention is to provide processes for thepreparation of 3,7-disubstituted-3-cephem-4-carboxylic acid compoundsand pharmaceutically acceptable salts thereof.

A further object of the present invention is to provide pharmaceuticalcomposition comprising, as active ingredients, said3,7-disubstituted-3-cephem-4-carboxylic acid compounds andpharmaceutically acceptable salts thereof.

Still further object of the present invention is to provide a method fortreatment of infectious diseases caused by pathogenic bacteria in humanbeing and animals.

The object 3,7-disubstituted-3-cephem-4-carboxylic acid compounds arenovel and can be represented by the following general formula (I):##STR2## in which R¹ is thiadiazolyl or isothiazolyl, each of which mayhave suitable substituent(s), or thiazolyl;

R² is hydrogen or lower alkyl;

R³ is carboxy or protected carboxy;

R⁴ is hydrogen, acyloxy or a heterocyclicthio group which may havesuitable substituent(s); and

R⁵ is hydrogen or lower alkoxy.

The 3,7-disubstituted-3-cephem-4-carboxylic-acid compounds (I) can beprepared by conventional processes applied in the cephalosporin field asillustrated by the following scheme. ##STR3## wherein R¹, R², R³, R⁴ andR⁵ are each as defined above; R^(2') is hydrogen, lower alkyl or ahydroxy protective group; and R^(3') is protected carboxy.

The starting compounds (III) and (IV) are novel and can be prepared bythe processes as illustrated by the following scheme. ##STR4## in whichR¹ and R² are each as defined above; R^(2") is lower alkyl;

R^(2'") is a hydroxy protective group;

R^(5') is an amino protective group; and

Z is protected carboxy.

The starting compound (IV) can be prepared by the Process 1 asillustrated above.

In the present invention, with regard to the object compounds (I) and(Ia), the starting compounds (III), (IIIa)-(IIId) and (IV) and the othercompounds (IV), (V), (VII), (VIII), (X),(XI),(XV) and (XVI), it is to beunderstood that all of said compounds include syn isomer, anti isomerand a mixture thereof. And, as to the object compounds (I) and (Ia), thesyn isomer thereof means one geometrical isomer having the grouprepresented by the following formula: ##STR5## and the anti isomer meansthe other geometrical isomer having the group of the formula: ##STR6##wherein R¹ and R² are each as defined above.

Further, as to the starting compounds and the other compounds, the synand anti isomers thereof also are represented by the same geometricalconfiguration as that of the object compound, respectively.

Suitable pharmaceutically acceptable salt of the object3,7-disubstituted-3-cephem-4-carboxylic acid compounds (I) areconventional non-toxic salts and may include a metal salt such as analkali metal salt (e.g., sodium salt, potassium salt, etc.) and analkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.),ammonium salt, an organic amine salt (e.g., trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, diethanolamine salt, etc.), anorganic acid salt (e.g., maleate, lactate, tartrate, methanesulfonate,benzenesulfonate, toluenesulfonete etc.), an inorganic acid salt (e.g.,hydrochloride, hydrobromide, sulfate, phosphate, etc.), or a salt withan amino acid (e.g., arginine, aspartic acid, lysine, glutamic acid,etc.), and the like.

In the above and subsequent description of the present specification,suitable examples and illustrations for the various definitions to beincluded within the scope thereof are explained in details as follows.

The term "lower" is intended to mean 1 to 6 carbon atom(s) unlessotherwise provided.

Suitable thiadiazolyl may include 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl and 1,3,4-thiadiazolyl.

Said thiadiazolyl and isothiazolyl for R¹ may have one or two suitablesubstituent(s) such as lower alkyl, halogen, hydroxy, amino, protectedamino or the like.

Suitable protected amino may include an acylamino, and an aminoprotected by a conventional protective group other than the acyl groupsuch as benzyl, diphenylmethyl, trityl or the like.

Suitable lower alkyl may include methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, hexyl and the like, and preferablyone having 1 to 4 carbon atom(s), and more preferably one having 1 to 2carbon atom(s).

Suitable halogen may include chlorine, bromine, fluorine and iodine.

Suitable protected carboxy and include esterified carboxy in which saidester may be the ones such as lower alkyl ester (e.g., methyl ester,ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester,1-cyclopropylethyl ester, etc.); lower alkenylester (e.g., vinyl ester,alkyl ester etc.); lower alkynyl ester (e.g., ethynyl ester, propynylester, etc.); mono(or di or tri)-halo(lower)alkyl ester (e.g.,2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.); loweralkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl ester,propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethylester, pivaloyloxymethyl ester, 2-acetoxyethyl ester,2-propionyloxyethyl ester, etc.); lower alkanesulfonyl(lower)alkyl ester(e.g., 2-mesylethyl ester etc.); ar(lower)alkyl ester, preferablymono(or di or tri)phenyl(lower)alkyl ester which may have one or moresuitable substituent(s) (e.g., benzyl ester, 4-methoxybenzyl ester,4-nitrobenzyl ester, phenethyl ester, trityl ester, diphenylmethylester, diphenylethyl ester, bis(methoxyphenyl)methyl ester,3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditertiarybutylbenzyl ester,etc.); aryl ester which may have one or more suitable substituent(s)(e.g., phenyl ester, tolyl ester, tertiarybutylphenyl ester, xylylestor, mesityl ester, cumenyl ester, etc.), and the like.

Preferable example of protected carboxy may be, more concretely, loweralkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,t-pentyloxycarbonyl, hexyloxycarbonyl, 1-cyclopropylethoxycarbonyl,etc.), and preferably one having 2 to 4 carbon atoms; or diphenyl(lower)alkoxycarbonyl having C₁₄ to C₁₉ carbon atoms (e.g.,diphenylmethoxycarbonyl, diphenylethoxycarbonyl, etc.), and preferablyone having C₁₄ to C₁₆ carbon atoms.

Suitable acyl moiety in the terms "acylamino" and "acyloxy" as mentionedabove may include carbamoyl in which the amino function may beprotected, aliphatic acyl group and acyl group containing an aromatic orheterocyclic ring. And, suitable examples of the said acyl may be loweralkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl,isovaleryl, oxalyl, succinyl, pivaloyl, etc.), and preferably one having1 to 3 carbon atom(s); lower alkoxycarbonyl (e.g., methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, 1-cyclopropylethoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), and preferably one having2 to 5 carbon atoms; lower alkanesulfonyl (e.g., mesyl, ethanesulfonyl,propanesulfonyl, isopropanesulfonyl, butanesulfonyl, etc.);arenesulfonyl (e.g., benzenesulfonyl, tosyl, etc.); aroyl (e.g.,benzoyl, toluoyl, naphthoyl, phthaloyl, indancarbonyl, etc.);ar(lower)alkanoyl (e.g., phenylacetyl, etc.), and the like. The acylmoiety as stated above may have one or two suitable substituent(s) suchas halogen (e.g., chlorine, bromine, iodine or fluorine), hydroxy,cyano, nitro, lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy,etc.); lower alkyl (e.g., methyl ethyl, propyl isopropyl, butyl, etc.),lower alkenyl (e.g., vinyl, allyl etc.), aryl (e.g., phenyl, tolyl,etc.) or the like.

Suitable example of the acyl having such substituent(s) may preferablybe halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl,trichloroacetyl, trifuoroacetyl, etc.), more preferably one having 2 to3 carbon atoms, and the like. Suitable protective group for amino in theabove acyl moiety (e.g. carbamoyl) may preferably be, for example, acylsuch as halo(lower)alkanoyl (e.g., chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, etc.) or the like.

Suitable heterocyclic moiety in the term "a heterocyclicthio group whichmay have suitable substituent(s)" means saturated or unsaturated,monocyclic or polycylic heterocyclic group containing at least onehetero-atom such as an oxygen, sulfur, nitrogen atom and the like. And,especially preferable heterocyclic group may be heterocyclic group suchas

unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl,pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl,triazolyl (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H-tetrazolyl,2H-tetrazolyl, etc.), etc; saturated 3 to 8-membered heteromonocyclicgroup containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl,imidazolidinyl, piperidino, piperazinyl, etc.; unsaturated condensedheterocyclic group containing 1 to 4 nitrogen atom(s), for example,indolyl, isoindolyl, indolizynyl, benzimidazolyl, quinolyl, isoquinolyl,idazolyl, benzotriazolyl, etc.; unsaturated 3- to 8-memberedheteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, (e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc.;saturated 3 to 8-membered heteromonocyclic group containing 1 to 2oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholinyl,etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygenatom(s) and 1 to 5 nitrogen atom(s), for example benzoxazolyl,benzoxadiazolyl, etc.; unsaturated 3 to 8-membered heteromonocyclicgroup containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample thiazolyl, thiadiazolyl (e.g., 1,2,4 -thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), etc; saturated 3 to8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1to 3 nitrogen atom(s), for example, thiazolidinyl, etc.; unsaturated 3to 8 membembered heteromonocyclic group containing a sulfur atom, forexample, thienyl, etc.; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), forexample, benzothiazolyl, benzothiadiazolyl, etc. and the like; whereinsaid heterocyclic group may have one or two suitable substituent(s) suchas lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl,pentyl, cyclopentyl, hexyl, cyclohexyl, etc.); lower alkenyl (e.g.,vinyl, allyl, butenyl, etc.); aryl (e.g., phenyl, tolyl, etc.); halogen(e.g., chlorine, bromine, iodine or fluorine); amino,di(lower)alkylamino(lower)alkyl(e.g.,dimethylaminomethyl,dimethylaminoethyl,diethylaminopropyl,diethylaminobutyl, etc.); or the like.

Suitable "hydroxy- and amino protective groups" may preferably be acylmoiety as exemplified above, respectively.

Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy and thelike, preferably one having 1 to 4 carbon atom(s), and more preferablyone having 1 to 2 carbon atom(s).

Preferred embodiments of the object compound (I) are as follows.

Preferred embodiment of R¹ is thiadiazolyl (more preferably1,2,3-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, etc.), whichmay have lower alkyl (preferably methyl, ethyl, etc.), or isothiazolyl;or thiazolyl; the preferred embodimet of R² is hydrogen or lower alkyl(preferably, methyl, ethyl, etc.); the preferred embodiment of R³ iscarboxy or diphenyl(lower)alkoxycarbonyl; the preferred embodiment or R⁴is hydrogen, acyloxy [preferably lower alkanoyloxy (e.g. acetoxy, etc.)or carbamoyloxy], thiadiazolylthio (more preferably1,3,4-thiadiazolylthio) which may have lower alkyl (preferably methyl,ethyl, etc.) or tetrazolylthio (more preferably 1H-tetrazolylthio)having lower alkyl (preferably methyl, ethyl, etc.),di(lower)alkylamino(lower)alkyl or lower alkenyl; and the preferredembodiment of R⁵ is hydrogen or lower alkoxy (preferably methoxy).

The processes for preparing the object compounds (I) and (Ia) areexplained in details in the following.

PROCESS 1

The object compound (I) can be prepared by reacting the compound (II) orits reactive derivative at the amino group or a salt thereof with thecompound (III) or its reactive derivative at the carboxy group or a saltthereof, and in case that the resulting compound has a protective groupon hydroxy in its hydroxyimino group, subjecting the resulting compoundto elimination reaction of the said protective group to provide thecompound (I) wherein R² is hydrogen.

Suitable reactive derivative at the amino group of the compound (II) mayinclude Schiff's base type imino or its tautomeric enamine typederivative formed by the reaction of the compound (II) with a carbonylcompound (e.g. aldehyde, ketone, etc.), isocyanate; a silyl derivativeformed by the reaction of the compound (II) with a silyl compound [e.g.bis(trimethylsilyl)acetamide, trimethylsilylacetamide, etc.]; aderivative formed by reaction of the compound (II) with phosphorustrichloride or phosgene, and the like.

Suitable salt of the compound (II) may include an acid addition saltsuch as an organic acid salt (e.g., acetate, maleate, tartrate,benzenesulfonate, toluenesulfonate, etc.) or an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.); a metalsalt (e.g., sodium salt, potassium salt, calcium salt, magnesium salt,etc.); ammonium salt; an organic amine salt (e.g., triethylamine salt,dicyclohexylamine salt, etc.), and the like.

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. The suitable example may be an acidchloride; an acid azide; a mixed acid anhydride with an acid such assubstituted phosphoric acid (e.g., dialkylphosphoric acid,phenylphosphoric acid, diphenylphoshoric acid, dibenzylphosphoric acid,halogenated phosphoric acid, etc.) dialkylphosphorous acid, sulfurousacid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, aliphaticcarboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid or trichloroacetic acid, etc.) or aromaticcarboxylic acid (e.g., benzoic acid, etc.); a symmetrical acidanhydride; an activated amido with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole or tetrazole; an activated ester [e.g.,cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl[(CH₃)₂ N⁺=CH--]ester, vinyl ester, propargyl ester, p-nitrophenyl ester,2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester,mesyl phenyl ester, phenylazophenyl ester, phenyl thioester,p-nitrophenyl thioester, p-crosyl thioester, carboxymethyl thioester,pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, oran ester with N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide or1-hydroxy-6-chloro-1H-benzotriazole, and the like. These reactivederivatives can be optionally selected from them according to the kindof the compound (III) to be used.

The salts of the compound (III) may be salts with an inorganic base suchas an alkali metal salts (e.g., sodium or potassium salt) or an alkalineearth metal salt (e.g., calcium or magnesium salt), a salt with anorganic base such as trimethylamine, triethylamine, dicyclohexylamine orthe like.

The reaction of the compound (II) with the compound (III) is usuallycarried out in a conventional solvent such as water, acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence to thereaction. Among these solvents, hydrophilic solvents may be used in amixture with water.

When the compound (III) is used in free acid form or its salt form inthe reaction, the reaction is preferably carried out in the presence ofa conventional condensing agent such as carbodiimidecompound(e.g.,N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinoethylcarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N,N'-diethylcarbodiimide,N,N'-diisopropylcarbodiimideN-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,etc.),N,N'-carbonylbis(2-methylimidazole),pentamethyleneketone-N-cyclohexylimine,diphenylketene-N-cyclohexylimino, alkoxyacetylene,1-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate,isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride,thionyl chloride, oxalyl chloride, triphenylphosphine,N-ethylbenzisoxazolium salt, N-ethyl-5-phenyl-isoxazolium-3'-sulfonate,1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole, Vilsmeierreagent [e.g.,(chloromethylene)dimethylammonium chloride, a compoundformed by the reaction of dimethylformamide with phosphorus oxychloride,etc.], or the like.

The reaction may be also carried out in the presence of an inorganic oran organic base such as an alkali metal bicarbonate, alkali metalcarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorphorine,N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline, or the like.When the base or the condensing agent is in liquid, it can be used alsoas a solvent. The reaction temperature is not critical, and the reactionis usually carried out under cooling or at ambient temperature.

In the present reaction, even when the compound (III), wherein R^(2') isa hydroxy protective group, is used as a starting compound, occasionallythe object compound (I), wherein R² is hydrogen, can be isolated fromthe reaction mixture depending on a kind of the hydroxy protectivegroup, reaction conditions and the like.

In case that the resulting compound obtained by this process has ahydroxy protective group on hydroxy in its hydroxyimino group, the saidprotective group is eliminated by a conventional method (e.g.hydrolysis, etc.) to provide the compound (I) wherein R² is hydrogen.That is, for example, the elimination of the said protective group isusually conducted by a method using acid (e.g. hydrochloric acid,hydrobromic acid, sulfuric acid, trifluoroacetic acid, etc.) or a base,for example, an inorganic base such as an alkali metal hydroxide (e.g.,sodium hydroxide, potassium hydroxide etc.), an alkali metal bicarbonate(e.g., sodium bicarbonate, potassium bicarbonate etc.) or an alkalimetal carbonate (e.g., sodium carbonate, potassium carbonate etc.), anorganic base such as an alkali metal alkoxide (e.g., sodium methoxide,sodium ethoxide etc.), a trialkylamine (e.g., trimethylamine,triethylamine etc.), triethanolamine, N,N-dimethylaniline,N,N-dimethylbenzylamine, N-methylmorpholine or pyridine; and anelimination reaction using silica gel, basic or acidic alumina, basic oracidic ion exchange resin, thiourea, trifluoroacetic acid/anisole,copper/dimethylformamide, zinc/dimethylformamide, zinc/acetic acid,zinc/formic acid, trifluoroacetic acid/zinc etc. The present eliminationreaction is usually carried out in water, hydrophilic solvent or amixture thereof. The reaction temperature is not critical and thereaction is preferably carried out at ambient temperature, or undercooling.

And, the protected carboxy group or salts in the compound (II) may betransformed into the corresponding free carboxy group in the course ofthe reaction and/or in post-treatment according to the reactionconditions.

The mode of reactions occured in the course of the acylation reactionand/or in post-treatment as mentioned above (i.e. transformation ofprotected carboxy group into the free carboxy group) is to be understoodto be included within the scope of the present invention.

In this process, there may occur partially or nearly completeisomerization between syn and anti geometry of the compound (III) in thecourse of the activation process thereof or the reaction with thecompound (II) (i.e. acylation), depending on surrounding such asreaction conditions or the like. Generally, such isomerization tends tobe equilibrated toward the more stable anti-geometry. Under suchchemical behaviors of the compound (III), in case of preparing the synisomer of the object compound (I) selectively and preparing it in goodyield, it is to be noted that it is essential to use syn isomer of thecompound (III) as a starting compound and to select the reactionconditions suitable for producing the syn isomer selectively and in goodyield. For example, for this purpose, the acylation reaction in thisprocess is more preferably conducted by reacting the compounds (II) and(III) in the presence of a condensing agent such as Vilsmeier reagent,etc. and in a reaction condition such as around neutral.

PROCESS 2

The object compound (Ia) or a salt thereof can be prepared by subjectingthe compound (IV) or a salt thereof to elimination reaction of thecarboxy protective group.

Suitable salt of the compound (IV) can be referred to the acid additionsalt exemplified for the compound (II).

In the present elimination reaction, all conventional methods used inthe elimination reaction of the carboxy protective group, for example,hydrolysis, reduction, etc. are applicable. When the carboxy protectivegroup is an ester, it can be eliminated by hydrolysis. The hydrolysis ispreferably carried out in the presence of a base or an acid. Suitablebase may include an inorganic base and an organic base as aforementionedin process 1.

Suitable acid may include an organic acid (e.g., formic acid, aceticacid, trifluoroacetic acid, propionic acid, etc.) and an inorganic acid(e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.).Trifluoroacetic acid may be used in the presence of anisole.

The present hydrolysis is usually carried out in an organic solvent,water or a mixed solvent thereof.

The reaction temperature is not critical, and it may be suitablyselected in accordance with the kind of the protective group of thecarboxy and the elimination method.

The reduction is carried out in a similar manner to that of process (D)as mentioned below in the part of preparations of the starting compound(III).

Processes for preparing the starting compund (III) are explained asfollows.

PROCESS (A): (IV)→(V) and (X)→(XI)

The compounds (V) and (XI) can be prepared by alkylating the compounds(IV) and (X), respectively.

The alkylating agent to be used in these alkylation reactions mayinclude di(lower)alkyl sulfate (e.g., dimethyl sulfate, diethyl sulfate,etc.), diazo(lower)alkane (e.g., diazomethane, diazoethane, etc.), loweralkyl halide (e.g., methyl iodide, ethyl iodide, etc.), lower alkylsulfonate (e.g., methyl p-toluenesulfonate, etc.), and the like.

The reaction by using di(lower)alkyl sulfate, lower alkyl halide orlower alkyl sulfonate is usually carried out in a solvent such as water,acetone, ethanol, ether, ethyl acetate, dimethylformamide or any othersolvent which does not adversely influence to the reaction, and ispreferably carried out in the presence of a base such as aforementionedinorganic or organic base. The reaction temperature is not critical andthe reaction is usually carried out under cooling to heating aroundboiling point of the solvent.

The reaction by using diazoalkane is usually carried out in a solventsuch as ether, tetrahydrofuran or the like. The reaction temperature isnot critical and the reaction is usually carried out under cooling or atambient temperature.

PROCESS (B): (B)+(VI)→(VII)

The compound (VII) can be prepared by reacting the compound (V) with thecompound (VI).

The present reaction is usually carried out in a solvent such as analcohol (e.g., methanol, ethanol, etc.), chloroform, water or any othersolvent which does not adversely affect the reaction. The reactiontemperature is not critical and the reaction is usually carried out atambient temperature or under warming.

PROCESS (C): (VII)→(VIII)

The compound (VIII) can be prepared by reacting the compound (VII) witha sulfurizating agent.

Suitable sulfurizating agent may include conventional ones, which cansulfurize an active methylene group, for example, sulfur, ammoniumsulfide, sulfur dihalide (e.g., sulfur dichloride, sulfur dibromide,etc.), thionyl halide (e.g., thionyl chloride, thionyl bromide, etc.) orthe like.

The reaction can be carried out with or without solvent, and as asolvent, there is used benzene, methylene chloride or any other solventwhich does not adversely affect the reaction. The reaction temperatureis not critical and the reaction is usually carried out at ambienttemperature, under warming or heating.

PROCESS (D): (VIII)→(III_(a)), (XI)→(III_(b)) and (XII)→(XIII)

The compound (III_(a)), (III_(b)) and (XIII) can be prepared bysubjecting the compound (VIII), (XI) and (XII) to elimination reactionof their carboxy protective group, respectively.

In the present elimination reaction, all conventional methods, forexample, hydrolysis, reduction, etc. can be applicable.

When the protected carboxy group is an ester, the protective group canbe eliminated preferably by hydrolysis. Hydrolysis is preferably carriedout in the presence of a base or an acid. Suitable base may include aninorganic base and an organic base such as an alkali metal (e.g.,sodium, potassium, etc.), an alkaline earth metal (e.g., magnesium,calcium, etc.), the hydroxide or carbonate or bicarbonate thereof,trialkylamine (e.g., trimethylamine, triethylamine, etc.), picoline,1,5-diazabicyclo[4,3,0]none-5-ene, 1,4-diazabicyclo[2,2,2]octane,1,8-diazabicyclo[5,4,0]undecene-7, or the like. Suitable acid mayinclude an organic acid (e.g., formic acid, acetic acid, propionic acid,trifluoroacetic acid, etc.) and an inorganic acid (e.g., hydrochloricacid, hydrobromic acid, sulfuric acid, etc.).

The reaction is usually carried out in a solvent such as water, analcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any othersolvent which does not adversely influence to the reaction. A liquidbase or acid can be also used as the solvent. The reaction temperatureis not critical and the reaction is usually carried out under cooling towarming.

Reduction can be applied preferably for elimination of the protectivegroup such as 2-iodoethyl, 2,2,2-trichloroethyl, or the like. Thereduction method applicable for the elimination reaction may include,for example, reduction by using a combination of a metal (e.g., zinc,zinc amalgam, etc.) or a salt of chrome compound (e.g., chromouschloride, chromous acetate, etc.) and an organic or inorganic acid(e.g., acetic acid, propionic acid, hydrochloric acid etc.); andconventional catalytic reduction in the presence of a conventionalmetallic catalyst.

PROCESS (E): (IX)→(X)

The compound (X) can be prepared by subjecting the compound (IX) tonitrosation.

The nitrosating agent to be used in the reaction is conventional ones,which can react with an active methylene compound to produce C-nitrosocompound, including for example, nitrous acid or its's salt such asalkali metal nitrite (e.g., sodium nitrite, etc.) or it's ester such aslower alkyl nitrite (e.g., tert-butyl nitrite, isopentyl nitrite, etc.),and the like.

The reaction, when a salt of nitrous acid is used as the nitrosatingagent, is usually carried out in the presence of an inorganic or organicacid such as hydrochloric acid, sulfuric acid, acetic acid or the like.On the contrary, when an ester of nitrous acid is used as thenitrosating agent, the reaction is preferably carried out in thepresence of a rather strong base such as an alkali metal alkoxide (e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.) andthe like.

The present reaction is usually carried out in a solvent such as water,acetic acid, alcohol (e.g., ethanol, methanol, etc.), ether,tetrahydrofuran or any other solvent which does not adversely influenceto the reaction. The reaction temperature is not critical and thereaction is usually carried out under cooling or at ambient temperature.

PROCESS (F): (IX)→(XII)

The compound (XII) can be prepared by oxidizing the compound (IX) withan oxidizing agent.

Suitable oxidizing agent is conventional ones, which can oxidize anactive methylene group into carbonyl group, including, for example,selenium dioxide, manganous acetate and potassium permanganate or thelike.

The reaction is usually carried out in a solvent which does notadversely influence to the reaction, for example, water, dioxane,pyridine, tetrahydrofuran, and the like. The reaction temperature is notcritical and the reaction is preferably carried out under warming toheating.

PROCESS (G): (X)→(XIII)

The compound (XIII) can be prepared by hydrolyzing the compound (X).

The hydrolyis is conventionally carried out, for example, in thepresence of alkali metal bisulfite (e.g., sodium bisulfite, etc.)titanium trichloride, hydrohalogenic acid (e.g., hydrochloric acidhydrobromic acid, etc.), formic acid, nitrous acid or the like, andpreferably hydrohalogenic acid may be used in the presence of analdehyde such as formaldehyde, etc.

The reaction is usually carried out in an aqueous solvent such as water,aqueous alcohol (e.g., methanol ethanol, etc.), aqueous acetic acid orany other aqueous solvent which does not adversely influence to thereaction. The reaction temperature is not critical and the reaction isusually carried out at ambient temperature, under warming or heating.

PROCESS (H): (XIII)+(XIV)→(III_(b))

The compound (III_(b)) can be prepared by reacting the compound (XIII)with the compound (XIV) or a salt thereof.

Suitable salt of the compound (XIV) may include an inorganic acid salt(e.g., hydrochloride, hydrobromide, sulfate, etc.), an organic acid salt(e.g., acetate, maleate, p-toluenesulfonate, etc.) and the like.

The reaction is usually carried out in a solvent such as water, analcohol (e.g., methanol, ethanol, etc.), a mixture thereof or any othersolvent which does not adversely influence to the reaction.

The reaction is preferably carried out in the presence of a base, forexample, an inorganic base such as alkali metal (e.g., sodium,potassium, etc.), alkaline earth metal (e.g., magnesium, calcium etc.),the hydroxide or carbonate or bicarbonate thereof or the like, and anorganic base such as alkali metal alkoxide (e.g., sodium methoxide,sodium ethoxide, etc.), trialkylamine (e.g. trimethylamine,triethylamine, etc.), N,N-dialkylamine (e.g., N,N-dimethylaniline,etc.), N,N-dialkylbenzylamine (e.g., N,N-dimethylbenzylamine, etc.),pyridine or the like.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to heating.

In this process, there may occasionally be given a mixture of syn andanti isomers of the compound (III_(b)) depending on the reactionconditions etc. to be used. Each of said syn and anti isomers can beseparated and isolated from such mixture according to conventionalseparation and isolation procedures, for example, esterification of saidmixture, separation of the esters into each of syn and anti isomers by,for example, chromatographical fractionation and then recovery of eachof the corresponding carboxylic acid from each of the separated syn andanti isomeric esters by hydrolyzing the said ester functions,respectively.

PROCESS (I): (XIII)→(III_(c))

The compound (III_(c)) can be prepared by reacting the compound (XIII)with hydroxylamine or a salt thereof.

Suitable salt of hydroxylamine can be referred to the ones exemplifiedfor the compound (XIV).

The reaction is preferably conducted substantially in the similar manneras that exemplified in the Process (H): (XIII)+(XIV)→(III_(b)). Thepresent reaction may preferably be carried out in the presence ofalkaline earth metal hydroxide (e.g., magnesium hydroxide, calciumhydroxide, etc.).

PROCESS (J): (III_(c))→(III_(d))

The compound (III_(d)) can be prepared by subjecting the compound(III_(c)) to introduction reaction of a protective group for hydroxy.

Suitable introducing agent may include an acylating agent which includesan aliphatic aromatic or heterocyclic carboxylic acid, and thecorresponding sulfonic acid, formic acid ester, isocyanic acid ester andcarbamic acid, and the corresponding thio acid thereof, and the reactivederivative of the above acids. Suitable reactive derivative of the aboveacids may include the same ones as illustrated in the explanation of"reactive derivative at the carboxy group of the compound (III)".

Examples of the protective group (e.g. acyl group) to be introduced intothe hydroxyimino group in the compound (III_(c)) may be referred to thesame one (e.g., acyl group) as illustrated in the explanation of theprotective group moiety (e.g., acyl moiety) for the term "acylamino".

The reaction is carried out substantially in the same manner asillustrated in the reaction of the compound (II) or its reactivederivative at the amino group or a salt thereof with the compound (III)or its reactive derivative at the carboxy group.

In the aforementioned reactions and/or the post-treating of thereactions of the present invention, the aforementioned syn or antiisomer may occasionally transformed into the other geometrical isomerand such cases are to be also included in the scope of the presentinvention.

In case that the object compound (I) is obtained in a form of the freeacid at 4 position and/or in case that the object compound (I) has freeamino group, it may be transformed into its pharmaceutically acceptablesalt as aforementioned by a conventional method.

The object compound (I) of the present invention exhibits highantimicrobial activity and inhibits the growth of a number ofmicroorganisms including pathogenic Gram-positive and Gram-negativebacteria. And, it is to be noted that, among the object compounds,particularly the syn isomer thereof is characterized by having higherantimicrobial activity.

For therapeutic administration, the cephalosporin compounds according tothe present invention are used in the form of pharmaceutical preparationwhich contain said compounds in admixture with a pharmaceuticallyacceptable carriers such as an organic or inorganic solid or liquidexcipient suitable for oral, parenteral or external administration. Thepharmaceutical preparations may be in solid for such as capsule, tablet,dragee, ointment or suppository, or in liquid form such as solution,suspension, or emulsion. If desired, there may be included in the abovepreparations auxiliary substances, stabilizing agents, wetting oremulsifying agents, buffers and other commonly used additives.

While the dosage of the compounds may vary from and also depend upon theage and condition of the patient, an average single dose of about 50mg., 100 mg., 250 mg., and 500 mg. of the compounds according to thepresent invention has proved to be effective for treating of infectiousdiseases causes by a number of pathogenic bacteria. In general amountsbetween 1 mg. and about 1000 mg. or even more may be administered perday.

Now, in order to show the utility of the object compounds (I), test dataon anti-microbial activity of some representative compounds of thepresent invention are shown below.

TEST COMPOUNDS

(1)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(2)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer)

(3)7-[2-Hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

(4)7-[2-Hydroxyimino-2-(isothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

TEST METHOD

In vitro antibacterial activity was determined by the two-foldagar-plate dilution method as described below.

One loopful of an overnight culture of each test strain inTrypticase-soy broth (10⁸ viable cells per ml.) was streaked on heartinfusion agar (III-agar) containing graded concentrations ofantibiotics, and the minimal inhibitory concentration (NIC) wasexpressed in terms of μg/ml. after incubation at 37° C. for 20 hours.

    ______________________________________                                        Test results                                                                                 MIC (μg/mL.)                                                               Test Compounds                                                 Test Bacteria    (1)    (2)      (3)  (4)                                     ______________________________________                                        Staph. aureus 209P JC-1                                                                        3.13   12.5     0.78 0.39                                    E. coli NIHJ JC-2                                                                              0.78   25       3.13 1.56                                    Sh. flexneri 2a  1.56   12.5     0.39 0.39                                    Sal. enteritidis 0.2    6.25     1.56 0.78                                    ______________________________________                                    

The following examples are given for the purpose of illustrating thepresent invention:

EXAMPLE 1 (a) Preparation of the starting compound

(1) Pulverized potassium carbonate (160 g.) was added to a solution ofethyl 2-hydroxyiminoacetoacetate (a mixture of syn and anti isomers)(152 g.) in acetone (500 ml.). Dimethyl sulfate (130 g.) was dropwiseadded thereto with stirring over 1 hour at 45° to 50° C. and the mixturewas stirred for 2 hours. An insoluble material was filtered off and thefiltrate was concentrated under reduced pressure. The filtered insolublematerial was dissolved in water (500 ml.) and this solution was added tothe residue. The mixture was extracted twice with ethyl acetate (300ml.). The extract was washed twice with water (200 ml.) and with asaturated sodium chloride aqueous solution (200 ml.) and dried overmagnesium sulfate. The solvent was distilled off under reduced pressureand the residue was distilled under reduced pressure to give colorlessoil of ethyl 2-methoxyiminoacetoacetate (a mixture of syn and antiisomers) (145.3 g.), bp 55° to 64° C./0.5 mm Hg.

I.R. spectrum (Film): 1745, 1695, 1600 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ), ppm: 4.33 (4H, q, J=8 Hz), 4.08 (3H, s),3.95 (3H, s), 2.40 (3H, s), 1.63 (3H, s), 1.33 (6H, t, J=8 Hz).

(2) A solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn andanti isomers) (34.6 g.) and t-butoxycarbonylhydrazine (26.4 g.) inethanol (200 ml.) was stirred for 7.5 hours at ambient temperature andallowed to stand overnight to precipitate crystals. The crystals werecollected by filtration, washed with ethanol and dried to give ethyl2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of syn andanti isomers) (41.7 g.), mp 144° to 145° C.

I.R. spectrum (Nujol): 3200, 1750, 1705, 1600, 1520 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 8.52 (1H, broad s), 4.35 (2H, q, J=7Hz), 4.10 (3H, s), 2.00 (3H, s), 1.50 (9H, s), 1.33 (3H, t, J=7 Hz).

(3) A mixture of ethyl2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of syn andanti isomers) (28.7 g.) and thionyl chloride (30 ml.) was warmed withstirring on a water bath of 50° C. for 3 minutes and then stirred for 5minutes at ambient temperature to give black solution. To the reactionmixture was added ethyl acetate (200 ml.) and the mixture was pouredinto ice-water (300 ml.). The ethyl acetate layer was separated, washedin turn with water, with a saturated aqueous solution of sodiumbicarbonate and with a saturated aqueous solution of sodium chloride.After drying over magnesium sulfate, the ethyl acetate solution wastreated with activated charcoal and concentrated to give black oil. Theoil was purified by column chromatography on silica gel using a mixtureof benzene and ethyl acetate (19:1) as an eluent to give ethyl2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (anti isomer) (4 g.).

I.R. spectrum (Film): 1730, 1590 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 9.38 (1H, s), 4.47 (2H, q, J=7 Hz), 4.20(3H, s), 1.40 (3H, t, J=7 Hz).

(4) Sulfur dichloride (15.9 ml.) was added with stirring at ambienttemperature to a solution of ethyl2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of syn andanti isomers) (14.36 g.) in methylene chloride (150 ml.), and themixture was stirred for 1 hour at ambient temperature. To the reactionmixture was added ice-water (300 ml.), and the methylene chloride layerwas washed with water, with a saturated aqueous solution of sodiumbicarbonate and with a saturated aqueous solution of sodium chloride anddried over magnesium sulfate. The solvent was distilled off to give anoil. The oil was purified by column chromatography on silica gel using amixture of benzene and n-hexane (19:1) as an eluent to firstly giveethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (syn isomer) (1.8g.), mp 77° to 79° C.

I.R. spectrum (Nujol): 1720, 1595 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 8.92 (1H, s), 4.46 (2H, q, J=7 Hz), 4.06(3H, s), 1.38 (3H, t, J=7 Hz).

From subsequent fractions, ethyl2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (anti isomer) (0.7 g.)was obtained as an oil.

I.R. spectrum (Film): 1730, 1590 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 9.38 (1H, s), 4.47 (2H, q, J=7 Hz), 4.20(3H, s), 1.40 (3H, t, J=7 Hz).

(5) A solution of sodium hydroxide (0.47 g.) in water (10 ml.) was addedto a solution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate(anti isomer) (2.1 g.) in methanol (20 ml.) and the resulting mixturewas stirred for 6 hours at ambient temperature. Methanol was removedfrom the reaction mixture and to the residue was added water. Theresulting mixture was washed with ether, adjusted to pH 1 with 10%hydrochloric acid and extracted twice with ether (50 ml.). The extractwas washed with a saturated aqueous solution of sodium chloride anddried over magnesium sulfate. The solvent was distilled off to give oilof 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer)(1.3 g.).

I.R. spectrum (Film): 2700-2200, 1715, 1600 cm⁻¹.

(b) Preparation of the object compound

A mixture of dimethylformamide (0.56 g.) and phosphorus oxychloride(1.17 g.) was warmed for 1 hour at 40° C. After cooling, methylenechloride (10 ml.) was added thereto and distilled off. The residue wassuspended in dry ethyl acetate (10 ml.). To the suspension was added asolution of 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (antiisomer) (1.3 g.) in dry ethyl acetate (10 ml.) with stirring andice-cooling, and the resulting mixture was stirred for 30 minutes at thesame temperature. On the other hand,7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(2.3 g.) was dissolved in a solution of trimethylsilylacetamide (5.9 g.)in dry ethyl acetate (40 ml.). To the solution was added theabove-obtained ethyl acetate solution with stirring at -20° C., and themixture was stirred for 1.5 hours at -10° to -20° C. After water (60ml.) was added to the reaction mixture at -20° C., precipitates werecollected by filtration and washed with acetone. The filtrate and thewashings were combined and the organic layer was separated. The aqueouslayer was extracted with ethyl acetate. The extract was combined withthe organic layer obtained above and the mixture was treated withactivated charcoal. The charcoal was filtered off and the filtrate wasadjusted to ph 7 with an aqueous solution of sodium bicarbonate afteradding water (100 ml.). The aqueous layer was separated and ethylacetate (100 ml.) was added thereto. The mixture was adjusted to pH 2with 10% hydrochloric acid and extracted with ethyl acetate. The aqueouslayer was further extracted with ethyl acetate (50 ml.). The ethylacetate extracts were combined, washed with a saturated aqueous solutionof sodium chloride and dried over magnesium sulfate. After the solventwas distilled off, ether was added to the residue to give powder. Thepowder was collected by filtration and dried to give7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer) (0.6 g.).

I.R. spectrum (Nujol): 3150, 1760, 1705, 1660, 1590, 1530 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.68 (1H, s), 9.58 (1H, d, J=8 Hz),9.51 (1H, s) 5.84 (1H, dd, J=5,8 Hz), 5.20 (1H, d, J=5 Hz), 4.45 (2H,AB_(q), J=13 Hz), 4.07 (3H, s), 3.72 (2H, AB_(q), J=17 Hz).

EXAMPLE 2 (a) Preparation of the starting compound

(1) A solution of ethyl 2-methoxyiminoacetoacetate (a mixture of syn andanti isomer) (226.6 g.) and acetohydrazide (78.5 g.) in ethanol (500ml.) was stirred for 1.5 hours at ambient temperature. Precipitates werecollected by filtration, washed with ethanol and ether and dried to giveethyl 2-methoxyimino-3-acetylhydrazonobutyrate (a mixture of syn andanti isomers) (155.7 g.), mp 190° to 191.5° C.

I.R. spectrum (Nujol): 3150, 1725, 1660, 1600, 1585 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 9.82 (1H, s), 4.32 (2H, q, J=7 Hz), 3.97(3H, s), 2.20 (3H, s), 2.10 (3H, s), 1.35 (3H, t, J=7 Hz).

(2) A mixture of ethyl 2-methoxyimino-3-acetylhydrazonobutyrate (amixture of syn and anti isomers) (22.9 g.) and thionyl chloride (51 g.)was warmed at 45° C. with stirring on water bath for 10 minutes. To thereaction mixture was added ethyl acetate (200 ml.) and the resultingmixture was poured into ice-water (300 ml.). The ethyl acetate layer wasseparated, in turn washed with water, with a saturated aqueous solutionof sodium bicarbonate and with a saturated aqueous solution of sodiumchloride and then dried over magnesium sulfate. After treating withactivated charcoal, the solvent was distilled off to give black oil. Theoil was purified by column chromatography on silica gel using benzene asan eluent to firstly give ethyl2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (syn isomer) (2 g.), mp77° to 79° C.

I.R. spectrum (Nujol): 1720, 1595 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 8.92 (1H, s), 4.46 (2H, q, J=7 Hz), 4.06(3H, s), 1.38 (3H, t, J=7 Hz).

From subsequent fractions, ethyl2-methoxyimino-2-(1,2,3-thiadiazol-4-yl) acetate (anti isomer) (6.4 g.)was obtained as an oil.

I.R. spectrum (Film): 1730, 1590 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 9.38 (1H, s), 4.47 (2H, q, J=7 Hz), 4.20(3H, s), 1.40 (3H, t, J=7 Hz).

(3) 1N Aqueous solution of sodium hydroxide (6.7 ml.) was added to asolution of ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (synisomer) (1.2 g.) in methanol (10 ml.) and the mixture was stirred for1.5 hours at ambient temperature. Methanol was distilled off from thereaction mixture and water was added to the residue. The mixture waswashed with ether, adjusted to pH 1 with 10% hydrochloric acid andextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium chloride and dried over magnesium sulfate.The solvent was distilled off to give prisms of2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.7g.), mp 110° to 113° C.

I.R. spectrum (Nujol): 2750-2150, 1730, 1595 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.47 (1H, s), 4.01 (3H, s).

(b) Preparation of the object compound

2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)-acetic acid (syn isomer) (0.6g.) and7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(1.1 g.) were reacted according to similar manners to those of Examples12 and 15 to give7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.7 g.), mp 90° to 98° C. (dec.).

I.R. spectrum (Nujol): 3250, 1780, 1725, 1680, 1530 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.82 (1H, d, J=8 Hz), 9.51 (1H, s),9.37 (1H, s), 5.88 (1H, dd, J=5,8 Hz), 5.20 (1H, d, J=5 Hz), 4.44 (2H,AB_(q), J=13 Hz), 3.99 (3H, s), 3.72 (2H, AB_(q), J=17 Hz).

EXAMPLE 3 (a) Preparation of the starting compound

(1) A sodium ethoxide solution which was prepared from sodium (230 mg.)and absolute ethanol (5 ml.) was dropwise added at 0° to 5° C. to asolution of ethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (1.86 g.)and isopentyl nitrite (3 ml.) in absolute ethanol (25 ml.). Theresulting mixture was stirred for 3 hours at the same temperature andfor 1 hour at ambient temperature. The reaction mixture was acidifiedwith 10% hydrochloric acid to precipitate crystals. After ethanol wasdistilled off under reduced pressure at 30° C., water (30 ml.) was addedto the residue, after which the mixture was extracted three times withethyl acetate (30 ml.). The extracts were washed with water and driedover sodium sulfate. The solvent was distilled off under reducedpressure to give crystals of ethyl2-hydroxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (a mixture ofsyn and anti isomers) (1.50 g.). The crystals were recrystallized fromethyl acetate to give pure crystals, mp 181° to 184° C. (dec.).

I.R. spectrum (Nujol): 3120, 2800-2100, 1742 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 4.37 (2H, q, J=7 Hz), 2.80 (3H, s),1.30 (3H, t, J=7 Hz).

(2) Potassium carbonate (2.85 g.) and dimethyl sulfate (2.2 g.) wereadded to a suspension of ethyl2-hydroxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (a mixture ofsyn and anti isomers) (3.7 g.) in ethyl acetate (60 ml.), and theresulting mixture was stirred for 6 hours at 40° to 45° C. The reactionmixture was washed with water (50 ml.) and dried over magnesium sulfate.The solvent was distilled off to give oil (2.5 g.). The oil was purifiedby column chromatography on silica gel using a mixture of benzene andethyl acetate (9:1) as an eluent to firstly give ethyl2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (syn isomer)(0.3 g.), mp 104° to 106° C.

I.R. spectrum (Nujol): 1735, 1590 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 4.42 (2H, q, J=7 Hz), 4.03 (3H, s),

2.77 (3H, s), 1.37 (3H, t, J=7 Hz).

From subsequent fractions, ethyl2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (anti isomer)(1.3 g.), mp 79° to 81° C., was obtained.

I.R. spectrum (Nujol): 1735, 1700, 1600 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm 4.42 (2H, q, J=7 Hz), 4.17 (3H, s), 2.82(3H, s), 1.37 (3H, t, J=7 Hz).

(3) Ethyl 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)-acetate (synisomer) (0.4 g.) and 1N aqueous solution of sodium hydroxide (2.1 ml.)were treated according to a similar manner to that of Example 1(a)(5) togive 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (synisomer) (0.25 g.), mp 168° to 171° C. (dec.).

I.R. spectrum (Nujol): 2750-2150, 1725, 1600 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 4.00 (3H, s), 2.74 (3H, s)

(b) Preparation of the object compound

2-Methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (synisomer) (0.21 g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid(0.41 g.) were reacted according to similar manners to those of Examples12 and 15 to give7-[2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxyicacid (syn isomer) (0.23 g.), mp 175° to 178° C. (dec.).

I.R. spectrum (Nujol): 3250, 1785, 1700, 1665, 1620, 1590, 1550 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.83 (1H, d, J=8 Hz), 9.57 (1H, s),5.87 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.43 (2H, AB_(q), J=13Hz), 4.00 (3H, s), 3.70 (2H, AB_(q), J=17 Hz), 2.77 (3H, s).

EXAMPLE 4 (a) Preparation of the starting compound

Ethyl 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (antiisomer) (1.2 g.) and 1N aqueous solution of sodium hydroxide (10.5 ml.)were treated according to a similar manner to that of Example 1(a)(5) togive 2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (antiisomer) (1.06 g.), mp 173° to 174° C. (dec.).

I.R. spectrum (Nujol): 2700-2150, 1660, 1540 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 4.12 (3H, s), 2.79 (3H, s).

(b) Preparation of the object compound

2-Methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetic acid (antiisomer) (0.99 g.) and7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(1.62 g.) were reacted according to a similar manner to that of Example1(b) to give7-[2-methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer) (1.25 g.), mp 110° to 115° C. (dec.).

I.R. spectrum (Nujol): 3200, 1780, 1730, 1680, 1630, 1530 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.74 (1H, d, J=8 Hz), 9.52 (1H, s),5.86 (3H, dd, J=5,8 Hz), 5.20 (1H, d, J=5 Hz), 4.45 (2H, AB_(q), J=13Hz), 4.16 (3H, s), 3.72 (2H, AB_(q), J=17 Hz), 2.90 (3H, s).

EXAMPLE 5 (a)

(1) Ethyl 2-(1,2,5-thiadiazol-3-yl)acetate (9.5 g.) and isopentylnitrite (10 ml.) were reacted according to a similar manner to that ofExample 3(a)(1) to give ethyl2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (a mixture of syn andanti isomers) (10.5 g.), mp 60° to 66° C.

I.R. spectrum (Nujol): 3150, 1710 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.27 (1H, s), 4.33 (2H, q, J=7 Hz),1.30 (3H, t, J=7 Hz).

(2) Ethyl 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (a mixture ofsyn and anti isomers) (10.4 g.) and dimethyl sulfate (6.5 g.) werereacted according to a similar manner to that of Example 3(a)(2) and theoil obtained was purified by column chromatography on silica gel usingbenzene as an eluent to firstly give oil of ethyl2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (syn isomer) (0.5 g.).

I.R. spectrum (Film): 1735, 1592 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 8.96 (1H, s), 4.50 (2H, q, J=7 Hz), 4.13(3H, s), 1.42 (3H, t, J=7 Hz),

From subsequent fractions, ethyl2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (anti isomer) (6.4 g.)was obtained as an oil.

I.R. spectrum (Film): 1730, 1585 cm⁻¹.

N.M.R spectrum (CDCl₃, δ) ppm: 9.05 (1H, s), 4.43 (2H, q, J=7 Hz), 4.20(3H, s), 1.40 (3H, t, J=7 Hz).

(3) Ethyl 2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (anti isomer)(3.0 g.) was treated with 1N aqueous solution of sodium hydroxide (16.8ml.) according to a similar manner to that of Example 1(a)(5) to give2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (anti isomer) (2.46g. ), mp 110° to 111° C.

I.R. spectrum (Nujol): 2700-2100, 1700, 1560 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.27 (1H, s), 4.07 (3H, s).

(b) Preparation of the object compound

2-Methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (anti isomer) (1.87g.) and 7-amino-3-(1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-b4-carboxylic acid (3.3 g.) were reacted according to a similar manner tothat of Example 1(b) to give powder of7-[2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer) (3.0 g.), mp 115° to 120° C. (dec.).

I.R. spectrum (Nujol): 3300, 1770, 1700, 1675, 1625, 1585 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.6 (1H, s), 9.55 (1H, d, J=8 Hz),9.30 (1H, s), 5.82 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.42 (2H,AB_(q), J=13 Hz), 4.10 (3H, s), 3.73 (2H, broad s).

EXAMPLE 6 (a) Preparation of the starting compound

(1) A solution of sodium (1.01 g.) in absolute methanol (10 ml.) wasdropwise added over 15 minutes with stirring and ice-cooling to asolution of methyl 2-(isothiazol-4-yl)acetate (6.30 g.) and isopentylnitrite (10.6 g.) in absolute methanol (63 ml.). The mixture was stirredfor 30 minutes at the same temperature and for 3 hours at ambienttemperature. The reaction mixture was concentrated and the residue waspoured into a mixture of ethyl acetate (50 ml.) and water (50 ml.) Theaqueous layer was separated and the ethyl acetate layer was extractedtwice with 1N aqueous solution of sodium hydroxide (20 ml. and 10 ml.).The extracts and the aqueous layer separated above were combined,adjusted to pH 1 with 10% hydrochloric acid and extracted twice withethyl acetate (70 ml. and 50 ml.). The extracts were washed with a 5%aqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride and dried over magnesium sulfate. The solvent wasdistilled off under reduced pressure to give methyl2-hydroxyimino-2-(isothiazol-4-yl)acetate (anti isomer) (4.55 g.), mp110° to 112° C.

I.R. spectrum (Nujol): 3230, 1730 cm⁻¹.

(2) A mixture of methyl 2-hydroxyimino-2-(isothiazol-4-yl)-acetate (antiisomer) (3.41 g.), 36% aqueous solution of formaldehyde (24 ml.), conc.hydrochloric acid (12 ml.) and water (24 ml.) was stirred for 7 hours at90° to 100° C. The reaction mixture was allowed to stand overnight in arefrigerator to precipitate crystals. The crystals were collected byfiltration, washed with a small amount of ice-water and then dried togive 2-(isothiazol-4-yl)glyoxylic acid (2.09 g.). The mother liquor wasextracted with ethyl acetate to give the same compound (0.34 g.), mp145° to 148° C.

I.R. spectrum (Nujol): 1720, 1675 cm⁻.

(3) A suspension of 2-(isothiazol-4-yl)glyoxylic acid (240 mg.),magnesium hydroxide (290 mg.) and hydroxylamino hydrochloride (140 mg.)in a mixture of ethanol (2 ml.) and water (10 ml.) was stirred for 2hours at ambient temperature and allowed to stand overnight at ambienttemperature. Ethanol was distilled off and to the residue was addedethyl acetate. The mixture was adjusted to pH 1 with 10% hydrochloricacid and the ethyl acetate layer was washed with water and dried overmagnesium sulfate. The solvent was distilled off under reduced pressureto give 2-hydroxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (0.20g.), mp 159° to 161° C. (dec.).

I.R. spectrum (Nujol): 3250, 3200, 1690 cm⁻¹.

(4) Dichloroacetyl chloride (3.58 g.) was added with stirring andice-cooling to a suspension of 2-hydroxyimino-2-(isothiazol-4-yl)aceticacid (syn isomer) (1.50 g.) in dry methylene chloride (40 ml.), and themixture was stirred for 2 hours at the same temperature. The reactionmixture was concentrated to the volume of 10 ml. Petroleum ether (50ml.) was added to the residue and the mixture was cooled in dryice-acetone bath. Precipitates were collected by filtration and washedwith petroleum ether to give2-dichloroacetoxyimino-2-(isothiazol-4-yl)acetic acid (syn isomer) (1.20g.).

(b) Preparation of the object compound

Thionyl chloride (770 mg.) was added to dimethylformamide (330 mg.), andthe resultant was stirred for 30 minutes at 40° C. The mixture wasconcentrated by dryness and the residue was suspended in methylenechloride (40 ml.). 2-Dichloroacetoxyimino-2-(isothiazol-4-yl)acetic acid(syn isomer) (1.20 g.) was added thereto at -10° to -15° C., and themixture was stirred for 30 minutes at the same temperature. In the otherhand, a suspension of7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (1.32 g.) and bis(trimethylsilyl)acetamide (3.2 g.) in drymethylene chloride (40 ml.) was stirred for 30 minutes at ambienttemperature to give clear solution. This solution was at once added at-40° C. to the methylene chloride solution obtained above, and themixture was stirred for 1 hour at -40° to -20° C. and for 1 hour at 0°to 5° C. The reaction mixture was concentrated, and to the residuecontaining7-[2-dichloroacetoxyimino-2-(isothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) were added ethyl acetate (100 ml.) and 5% hydrochloricacid (50 ml.). The ethyl acetate layer was separated, washed with waterand dried over magnesium sulfate. The solvent was distilled off to give7-[2-hydroxyimino-2-(isothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (860 mg.). This compound was dissolved in acetone (20ml.) and the solution was chromatographed on activated charcoal usingacetone as an eluent. Acetone was distilled off from the eluate, and theresidue was pulverized with ether to give pure object compound (400mg.), mp 113° to 116° C. (dec.).

I.R. spectrum (Nujol): 3250, 1790, 1700, 1660 cm⁻¹.

N.M.R. spectrum (d₆ -acetone+D₂ O, δ) ppm: 9.16 (1H, s), 8.78 (1H, s),6.00 (1H, d, J=5 Hz), 5.25 (1H, d, J=5 Hz), 4.43 (2H, s),

4.00 (3H, s), 3.80 (2H, s).

EXAMPLE 7 (a) Preparation of the starting compound

(1) A mixture of methyl 2-(1,2,5-thiadiazol-3-yl)acetate (25.0 g.) andselenium dioxide (52.6 g.) in a mixture of water (15.8 ml.) and dioxane(158 ml.) was stirred for 45 hours at 120° C. and precipitates werefiltered off. The filtrate was concentrated under reduced pressure togive crude methyl 2-(1,2,5-thiadiazol-3-yl)glyoxylate. To this compoundwere added methanol (500 ml.) and 2N aqueous solution of sodiumhydroxide (99 ml.). The mixture was stirred for 2.5 hours. Methanol wasdistilled off, and ethyl acetate and conc. hydrochloric acid were addedthereto to acidify. The resulting mixture was extracted with ethylacetate. The extract was washed, dried and concentrated. The residue(14.5 g.) was added to a solution of ethanol (920 ml.) and 1N aqueoussolution of potassium hydroxide (92 ml.). The resultant mixture wasstirred for 30 minutes, and precipitates were collected by filtrationand washed with ethanol to give potassium2-(1,2,5-thiadiazol-3-yl)glyoxylate. This compound was added to amixture of conc. hydrochloric acid (10 ml.), water (30 ml.) and ethylacetate (100 ml.), and extracted with the ethyl acetate. The aqueouslayer was further extracted with ethyl acetate after salting-out. Bothextracts were combined and an insoluble material was filtered off. Thefiltrate was dried over magnesium sulfate and concentrated to give2-(1,2,5-thiadiazol-3-yl)glyoxylic acid (12 g.).

I.R. spectrum (Nujol): 1700 cm⁻¹.

N.M.R. spectrum (D₂ O+KOH, δ) ppm: 8.7 (1H, s).

(2) 2-(1,2,5-Thiadiazol-3-yl)glyoxylic acid (7.4 g.) and hydroxylaminehydrochloride (3.1 g.) were reacted in the presence of magnesiumhydroxide (4.7 g.) according to a similar manner to that of Example6(a)(3) to give 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (synisomer) (7.5 g.).

I.R. spectrum (Nujol): 1700 cm⁻¹.

N.M.R. spectrum (d₆ -acetone, δ) ppm: 9.08 (1H, s).

(3) 2-Hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer)(4.8 g.) and dichloroacetyl chloride (9.2 g.) were reacted according toa similar manner to that of Example 6(a)(4) to give crystals of2-dichloroacetoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer)(3.7 g.).

I.R. spectrum (Nujol): 1780, 1755 cm⁻¹.

(b) Preparation of the object compound

Phosphorus pentachloride (2.5 g.) was added with stirring andice-cooling to a suspension of2-dichloroacetoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer)(3.7 g.) in dry methylene chloride (100 ml.), and the mixture wasstirred for 1 hour at ambient temperature. The resultant mixture wasconcentrated and benzene was added thereto and distilled off (twicerepeated). The residue was dissolved in dry methylene chloride. Thesolution was dropwise added with stirring and ice-cooling to a solutionof 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (3.9 g.) and bis(trimethylsilyl)acetamide (12 ml.) in dry methylenechloride (200 ml.). The resultant mixture was stirred for 1 hour at thesame temperature and for 1 hour at ambient temperature. Methylenechloride was distilled off and to the residue were added ethyl acetateand water. After an insoluble material was filtered off, the ethylacetate layer in the filtrate was washed three times with water, with asaturated aqueous solution of sodium chloride and dried over magnesiumsulfate. The solvent was distilled off to give a residue (4.5 g.). Theresidue containing7-[2-dichloroacetoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) was dissolved in a mixture of water and acetone, andthe solution was stirred for 2 hours at ambient temperature andextracted with ethyl acetate. The extract was washed with water and witha saturated aqueous solution of sodium chloride, and dried overmagnesium sulfate. The solvent was distilled off and the residue wasdissolved in ethyl acetate. The solution was chromatographed on silicagel (5 g.) and the eluate was concentrated. The residue wasreprecipitated from a mixture of ethyl acetate and ether, and theprecipitates were collected by filtration, washed with ether and dried(3 g.). The powder was dissolved in distillated acetone, and thesolution was treated with activated charcoal (3 g.) in column and thenconcentrated. The residue was reprecipitated from a mixture of acetoneand ether. The precipitates was collected by filtration, washed withether and dried to give7-[2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (2.5 g.), mp 155° to 160° C. (dec.).

N.M.R. spectrum (d₆ -acetone+D₂ O, δ) ppm: 9.00 (1H, s), 5.30 (1H, d,J=4.5 Hz), 5.07 (1H, d, J=4.5 Hz), 4.43 (2H, s), 4.03 (3H, s), 3.87 (2H,s).

EXAMPLE 8

Dimethylformamide (0.43 g.) was added to dry ethyl acetate (2 ml.), andphosphorus oxychloride (0.9 g.) was added thereto with stirring under10° C. To the mixture were added dry ethyl acetate (10 ml.) and2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1 g.)at 0° C., after which the resulting mixture was stirred for 30 minutesat the same temperature. On the other hand, trimethylsilylacetamide (6g.) was added to a suspension of 7-aminocephalosporanic acid (1.58 g.)in dry ethyl acetate (30 ml.) and the resulting mixture was stirred for1 hour at 40° C. to give clear solution. To this solution was dropwiseadded at -20° C. the above obtained ethyl acetate solution, after whichthe mixture was stirred for 1 hour at the same temperature. Water (20ml.) was added thereto and the ethyl acetate layer was separated aftershaking the mixture. The ethyl acetate layer was washed with water, andwater (30 ml.) was added thereto. The mixture was adjusted to pH 7.5with sodium bicarbonate and extracted. The aqueous layer was separatedand ethyl acetate (50 ml.) was added thereto. The resulting mixture wasadjusted to pH 2 with stirring with diluted hydrochloric acid andextracted with ethyl acetate. The extract was washed with water and witha saturated aqueous solution of sodium chloride, and dried overmagnesium sulfate. The solution was treated with activated charcoal andconcentrated under reduced pressure. The residue was pulverized withether and, the powder was collected by filtration and dried to give paleyellow powder of7-[2-methosyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]cephalosporanicacid (anti isomer) (0.8 g.).

I.R. spectrum (Nujol): 3300, 1780, 1730, 1680, 1640 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, s), 9.60 (1H, d, J=8 Hz),5.88 (1H, dd, J=5,8 Hz), 5.23 (1H, d, J=5 Hz), 4.87 (2H, AB_(q), J=13Hz), 4.07 (3H, s), 3.60 (2H, AB_(q), J=17 Hz), 2.04 (3H, s).

EXAMPLE 9

2-Methoxyiminio-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1.0g.) and7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (2.16 g.) were reacted according to similar manners to those ofExamples 1(b) and 8 to give pale yellow powder of7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer) (1.68 g.), mp 104° to 115° C. (dec.).

I.R. spectrum (Nujol): 3350, 1785, 1730 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, s), 9.61 (1H, d, J=8 Hz),5.84 (1H, dd, J=5,8 Hz), 5.15 (1H, d, J=5 Hz), 4.38 (2H, AB_(q), J=13Hz), 4.07 (3H, s), 3.70 (2H, broad s), 2.67 (3H, s).

EXAMPLE 10

2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (anti isomer) (1 g.)and7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (1.9 g.) were reacted according to similar manners to those ofExamples 1(b) and 8 to give pale yellow powder of7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer) (1.5 g.).

I.R. spectrum (Nujol): 3300, 1790, 1730, 1690, 1630 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.78 (1H, s), 9.66 (1H, d, J=8 Hz),5.83 (1H, dd, J=5,8 Hz), 5.17 (1H, d, J=5 Hz), 4.33 (2H, broad s), 4.10(3H, s), 3.93 (3H, s), 3.69 (2H, broad s).

EXAMPLE 11 (a) Preparation of the starting compound

(1) A mixture of ethyl 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate(a mixture of syn and anti isomers) (6.0 g.), 36% aqueous solution offormaldehyde (40 ml.), conc. hydrochloric acid (20 ml.) and water (40ml.) was treated according to a similar manner to that of Example6(a)(2) to give crystals of 2-(1,2,5-thiadiazol-3-yl)glyoxylic acid (1.6g.), mp 130° to 133° C.

(2)(i) Phenolphthalein indicator (3 drops) was added to a solution ofO-methylhydroxylamine hydrochloride (0.95 g.) in dry methanol (10 ml.).To the solution was dropwise added with stirring at ambient temperature1N methanol solution of sodium methoxide (11 ml.) until the color of thesolution was changed to purplish red. O-Methylhydroxylaminehydrochloride was added thereto by small portions until the solution waschanged to colorless solution. The mixture was stirred for 30 minutes atambient temperature. After precipitating sodium chloride was filteredoff, 2-(1,2,5-thiadiazol-3-yl)glyoxylic acid (1.5 g.) was added to thefiltrate and the mixture was stirred for 50 minutes at ambienttemperature. After methanol was distilled off at low temperature, waterwas added to the residue. The mixture was adjusted to pH 7.5 with anaqueous solution of sodium bicarbonate and washed with ether. Theaqueous layer was adjusted to pH 1.5 with 10% hydrochloric acid,subjected to salting-out and extracted with ether. The extract waswashed with a saturated aqueous solution of sodium chloride and driedover magnesium sulfate. Ether was distilled off at low temperature togive 2-methoxyimino-2(1,2,5-thiadiazol-3-yl)acetic acid (a mixture ofsyn and anti isomers) (1.5 g.)

(ii) This material was dissolved in ether (15 ml.) and a solution ofdiazomethane in ether was gradually added thereto under ice-coolinguntil the color of the mixture was changed to yellow. Acetic acid wasimmediately added thereto and the mixture was washed with a sodiumbicarbonate aqueous solution and a saturated sodium chloride aqueoussolution and dried over magnesium sulfate. Ether was distilled off togive oily residue. The oily residue was chromatographed on silica gelusing benzene as an eluent. Firstly the eluate containing syn isomer waseluted and the eluate was collected and concentrated to give oily methyl2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (syn isomer) (0.9 g.).

I.R. spectrum (Film): 1740, 1590 cm⁻¹.

N.M.R. spectrum (CDCl₃, δ) ppm: 8.92 (1H, s), 4.09 (3H, s), 3.96 (3H,s).

After the eluate containing syn isomer was eluted, then the eluatecontaining anti isomer was eluted. The eluate was collected andconcentrated to give oily methyl2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (anti isomer) (0.5 g.).

I.R. spectrum (Film: 1740, 1590 cm⁻¹.

(iii) An aqueous solution of 1N sodium hydroxide (5.4 ml.) was addedwith stirring at ambient temperature to a solution of methyl2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (syn isomer) (0.9 g.) inmethanol (10 ml.) and the mixture was stirred for 1 hour at ambienttemperature. Methanol was distilled off and water was added to theresidue, after which the mixture was washed with ether. The aqueouslayer was adjusted to pH 1.5 with 10% hydrochloric acid, subjected tosalting-out and extracted with ether. The extract was washed with asaturated aqueous solution of sodium chloride and dried over magnesiumsulfate. Ether was distilled off. Benzene was added to the residue andremoved to give crystals of2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (0.67g.), mp 99° to 100° C.

I.R. spectrum (Nujol): 2650-2150, 1735, 1690, 1600 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: (9.15 (1H, s), 4.05 (3H, s).

(b) Preparation of the object compound

2-Methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetic acid (syn isomer) (0.6g.) and7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid(1.16 g.) were reacted according to similar manners to those of Examples12 and 15 to give7-[2-methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.10 g.), mp 111° to 120° C.

I.R. spectrum (Nujol): 3300, 1770, 1725, 1670, 1620, 1550 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.77 (1H, d, J=8 Hz), 9.58 (1H, s),9.13 (1H, s), 5.85 (1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.43 (2H,AB_(q), J=13 Hz), 4.02 (3H, s), 3.68 (2H, broad s).

EXAMPLE 12

Dimethylformamide (0.34 g) was added to dry ethyl acetate (1 ml), andthen phosphorus oxychloride (0.72 g) was added thereto under 10° C. Themixture was stirred at -5° C. to solidify. Dry ethyl acetate (10 ml) wasadded thereto and 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid(syn isomer)(0.8 g) was added to the mixture at 0° C., after which theresulting mixture was stirred for 30 minutes at the same temperature. Onthe other hand, trimethylsilylacetamide (4.9 g) was added to asuspension of 7-aminocephalosporanic acid (1.28 g) in dry ethyl acetate(30 ml), and the mixture was stirred for 1 hour at 40° C. to give aclear solution. To this solution was dropwise added at -20° C. theabove-obtained ethyl acetate solution, and the mixture was stirred for 1hour at the same temperature. Water (20 ml) was added to the reactionmixture, and the resulting mixture was shaken enough. The ethyl acetatelayer was separated, washed with water and water (30 ml) was added tothe ethyl acetate solution. The mixture was adjusted to pH 7.5 withsodium bicarbonate and washed with ethyl acetate. The aqueous layer wasadjusted to pH 2 with dilute hydrochloric acid with stirring afteraddition of ethyl acetate (50 ml). The ethyl acetate layer was washedwith water and with a saturated aqueous solution of sodium chloride, anddried over magnesium sulfate. After treating with activated charcoal,the solvent was distilled off under reduced pressure. The residue waspulverized with ether to give pale yellow powder of7-[2-methylimino-2-(1,2,3-thiadiazol-4-yl)acetamido]cephalosporanic acid(syn isomer)(1.2 g).

I.R. spectrum (Nujol): 3300, 1790, 1735, 1680 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) 9.83 (1H, d, J=8 Hz), 9.40 (1H, s), 5.86(1H, dd, J=5,8 Hz), 5.18 (1H, d, J=5 Hz), 4.83 (2H, AB_(q), J=14 Hz),3.97 (3H, s), 3.55 (2H, broad s), 2.00 (3H, s).

EXAMPLE 13

2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer)(3.74 g)and 7-amino-3-methyl-3-cephem-4-carboxylic acid (4.3 g) were reactedaccording to similar manners to those of Examples 12 and 15 to give7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer)(5.0 g), mp 111° to 116° C. (dec.).

I.R. spectrum (Nujol): 3300, 1785, 1720, 1660, 1600, 1548 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ): 9.77 (1H, d, J=8 Hz), 9.37 (1H, s), 5.78(1H, dd, J=5,8 Hz) 5.11 (1H, d, J=5 Hz), 3.97 (3H, s), 3.45 (2H, AB_(q),J=17 Hz), 2.00 (3H, s).

EXAMPLE 14

2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer)(0.65 g)and 7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (0.96 g)were reacted according to similar manners to those of Examples 12 and 15to give7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer)(0.7 g).

I.R. spectrum (Nujol): 3250, 1780, 1720, 1670 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ): 9.77 (1H, d, J=9 Hz), 9.36 (1H, s), 6.54(2H, s), 5.87 (1H, dd, J=5,9 Hz), 5.16 (1H, d, J=5 Hz), 4.74 (2H,AB_(q), J=13 Hz), 3.96 (3H, s), 3.51 (2H, broad s).

EXAMPLE 15

Dimethylformamide (0.34 g.) was added to dry ethyl acetate (1 ml.), andthen phosphorus oxychloride (0.72 g.) was added thereto under 10° C. Themixture was stirred at -5° C. to solidify. Dry ethyl acetate (10 ml.)was added thereto and 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)aceticacid (syn isomer) (0.8 g.) was added to the mixture at 0° C., afterwhich the resulting mixture was stirred for 30 minutes at the sametemperature. On the other hand, trimethylsilylacetamide (4.9 g.) wasadded to a suspension of7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (1.54 g.) in dry ethyl acetate (30 ml.), and the mixture wasstirred for 1 hour at 40° C. to give a clear solution. To this solutionwas added dropwise at -20° C. the above-obtained ethyl acetate solution,and the mixture was stirred for 1 hour at the same temperature. Thereaction mixture was post-treated according to a similar manner to thatof Example 12 to give pale yellow powder of7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.9 g.).

I.R. spectrum (Nujol): 3300, 1780, 1730, 1680, 1630 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.89 1H, d, J=8 Hz), 9.40 (1H, s),5.88 (1H, dd, J=5,8 Hz), 5.20 (1H, d, J=5 Hz), 4.33 (2H, broad s), 4.01(3H, s), 3.93 (3H, s), 3.73 (2H, broad s).

EXAMPLE 16

2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (350mg.) and 7-amino-3-[1-(2-dimethylaminoethyl)-1H,tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (600 mg.) werereacted according to similar manners to those of Examples 12 and 15 togive7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (230 mg.).

I.R. spectrum (Nujol): 1775, 1670, 1605 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.85 (1H, d, J=8 Hz), 9.43 (1H, s),5.83 (1H, dd, J=5,8 Hz), 5.15 (1H, d, J=5 Hz), 4.37 (2H, t, J=5 Hz),4.30 (2H, broad s), 3.98 (3H, s), 3.65 (2H, broad s), 3.05 (2H, t, J=5Hz), 2.38 (6H, s).

EXAMPLE 17

Dicyclohexylcarbodiimide (0.99 g.) was added at ambient temperature to asolution of diphenylmethyl7-amino-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(2.1 g.) in dry tetrahydrofuran (20 ml.) and then2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetic acid (syn isomer) (0.9 g)was added thereto at ambient temperature to give white precipitates.After stirring for 2 days at ambient temperature, the precipitates werefiltered off and the filtrate was concentrated under reduced pressure togive brown oil. The oil as subjected to column chromatography on silicagel, eluted with a mixture of chloroform and ethyl acetate and theeluate was concentrated under reduced pressure to give diphenylmethyl7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer) (1.78 g.).

I.R. spectrum (Nujol) 3300, 1780, 1720, 1690 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 10.24 (1H, s), 9.37 (1H, s),7.06-7.72 (10H, m), 6.82 (1H, s), 5.19 (1H, s), 4.22 (2H, broad s), 3.94(3H, s), 3.79 (3H, s), 3.64 (2H, broad s), 3.48 (3H, s).

EXAMPLE 18

Anisole (0.86 ml.) was added at ambient temperature to a solution ofdiphenylmethyl7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate(syn isomer) (0.86 g.) in dry 1,2-dichloroethane (10 ml.), and thentrifluoroacetic acid (1.68 g.) was added dropwise thereto underice-cooling. The resulting mixture was stirred for 2 hours underice-cooling and the reaction mixture was concentrated under reducedpressure. To the residue were added ethyl acetate (20 ml.) and water (20ml.). After shaking the mixture, the ethyl acetate layer was separated.The remaining aqueous layer was further extracted with ethyl acetate (10ml. and 5 ml.). The ethyl acetate layers were combined and 10% aqueoussolution of dipotassium hydrogen phosphate (20 ml.) was added thereto.The mixture was shaken and the aqueous layer was separated. The ethylacetate layer was further extracted with 10% aqueous solution ofdipotassium hydrogen phosphate (10 ml. and 5 ml.). The aqueous layerswere combined and washed in turn with ethyl acetate (10 ml. and 5 ml.)and ether (10 ml.). Two remaining solvent in the aqueous layer wasremoved by bubbling of nitrogen gas. The resulting aqueous layer wasadjusted to pH 2 with 10% hydrochloric acid under ice-cooling.Precipitates were collected by filtration, washed with water and driedover phosphorus pentoxide under reduced pressure to give7-[2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-7-methoxy-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (0.21 g.).

I.R. spectrum (Nujol): 3250, 1780, 1730, 1690 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 10.22 (1H, s), 9.27 (1H, s), 5.17(1H, s), 4.22, 4.4 (2H, AB_(q), J=13 Hz), 4.01 (3H, s), 3.94 (3H, s),3.90 (2H, s), 3.52 (3H, s).

EXAMPLE 19

The following compounds were obtained according to a similar manner tothat of Example 18.

(1)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer).

I.R. spectrum (Nujol): 3150, 1760, 1705, 1660, 1590, 1530 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.68 (1H, s), 9.58 (1H, d, J=8 Hz),9.51 (1H, s), 5.84 (1H, dd, J=5, 8 Hz), 5.20 (1H, d, J=5 Hz), 4.45 (2H,AB_(q), J=13 Hz), 4.07 (3H, s), 3.72 (2H, AB_(q), J=17 Hz).

(2)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)-acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 90° to 98° C. (dec.).

I.R. spectrum (Nujol): 3250, 1780, 1725, 1680, 1530 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.82 (1H, d, J=8 Hz), 9.51 (1H, s),9.37 (1H, s), 5.88 (1H, dd, J=5, 8 Hz), 5.20 (1H, d, J=5 Hz), 4.44 (2H,AB_(q), J=13 Hz), 3.99 (3H, s), 3.72 (2H, AB_(q), J=17 Hz).

(3)7-[2-Methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 175° to 178° C. (dec.).

I.R. spectrum (Nujol): 3250, 1785, 1700, 1665, 1620, 1590, 1550 cm⁻¹

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.83 (1H, d, J=8 Hz), 9.57 (1H, s),5.87 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.43 (2H, AB_(q), J=13Hz), 4.00 (3H, s), 3.70 (2H, AB_(q), J=17 Hz), 2.77 (3H, s).

(4)7-[2-Methoxyimino-2-(5-methyl-1,3,4-thiadiazol-2-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer), mp. 110° to 115° C. (dec.).

I.R. spectrum (Nujol): 3200, 1780, 1730, 1680, 1630, 1530 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.74 (1H, d, J=8 Hz), 9.52 (1H, s),5.86 (1H, dd, J=5, 8 Hz), 5.20 (1H, d, J=5 Hz), 4.45 (2H, AB_(q), J=13Hz), 4.10 (3H, s), 3.72 (2H, AB_(q), J=17 Hz), 2.90 (3H, s).

(5)7-[2-Methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer), mp 115° to 120° C. (dec.).

I.R. spectrum (Nujol): 3300, 1770, 1700, 1675, 1625, 1585 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.6 (1H, s), 9.55 (1H, d, J=8 Hz),9.30 (1H, s), 5.82 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.42 (2H,AB_(q), J=13 Hz), 4.10 (3H, s), 3.73 (2H, broad s).

(6)7-[2-Hydroxyimino-2-(isothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol): 3250, 1790, 1700, 1660 cm⁻¹.

N.M.R. spectrum (d₆ -acetone+D₂ O, δ) ppm: 9.16 (1H, s), 8.78 (1H, s),6.00 (1H, d, J=5 Hz), 5.25 (1H, d, J=5 Hz), 4.43 (2H, s), 4.00 (3H, s),3.80 (2H, s).

(7)7-[2-Hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp 155° to 160° C. (dec.).

N.M.R. spectrum (d₆ -acetone+D₂ O, δ) ppm: 9.00 (1H, s), 5.30 (1H, d,J=4.5 Hz), 5.07 (1H, d, J=4.5 Hz), 4.43 (2H, s), 4.03 (3H, s), 3.87 (2H,s).

(8) 7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]cephalosporanicacid (anti isomer).

I.R. spectrum (Nujol): 3300, 1780, 1730, 1680, 1640 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, s), 9.60 (1H, d, J=8 Hz),5.88 (1H, dd, J=5, 8 Hz), 5.23 (1H, d, J=5 Hz), 4.87 (2H, AB_(q), J=13Hz), 4.07 (3H, s), 3.60 (2H, AB_(q), J=17 Hz), 2.04 (3H, s).

(9)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer), mp. 104° to 115° C. (dec.).

I.R. spectrum (Nujol): 3350, 1785, 1730 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.72 (1H, s), 9.61 (1H, d, J=8 Hz),5.84 (1H, dd, J=5, 8 Hz), 5.15 (1H, d, J=5 Hz), 4.38 (2H, AB_(q), J=13Hz), 4.07 (3H, s), 3.70 (2H, broad s), 2.67 (3H, s).

(10)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (anti isomer).

I.R. Spectrum (Nujol): 3300, 1790, 1730, 1690, 1630 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.78 (1H, s), 9.66 (1H, d, J=8 Hz),5.83 (1H, dd, J=5, 8 Hz), 5.17 (1H, d, J=5 Hz), 4.33 (2H, broad s), 4.10(3H, s), 3.93 (3H, s), 3.69 (2H, broad s).

(11)7-[2-Methoxyimino-2-(1,2,5-thiadiazol-3-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer), mp. 111° to 120° C.

I.R. spectrum (Nujol): 3300, 1770, 1725, 1670, 1620, 1550 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.77 (1H, d, J=8 Hz), 9.58 (1H, s),9.13 (1H, s), 5.85 (1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.43 (2H,AB_(q), J=13 Hz), 4.02 (3H, s), 3.68 (2H, broad s).

(12)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]cephalosporanicacid (syn isomer).

I.R. spectrum (Nujol): 3300, 1790, 1735, 1680 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ): 9.83 (1H, d, J=8 Hz), 9.40 (1H, s), 5.86(1H, dd, J=5, 8 Hz), 5.18 (1H, d, J=5 Hz), 4.83 (2H, AB_(q), J=14 Hz),3.97 (3H, s), 3.55 (2H, broad s), 2.00 (3H, s).

(13)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-methyl-3-cephem-4-carboxylicacid (syn isomer), mp 111° to 116° C. (dec.).

I.R. spectrum (Nujol): 3300, 1785, 1720, 1660, 1600 1548 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ): 9.77 (1H, d, J=8 Hz), 9.37 (1H, s), 5.78(1H, dd, J=5, 8 Hz), 5.11 (1H, d, J=5 Hz), 3.97 (3H, s), 3.45 (2H,AB_(q), J=17 Hz), 2.00 (3H, s).

(14)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-carbamoyloxymethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol): 3250, 1780, 1720, 1670 cm⁻¹. N.M.R. spectrum (d₆-DMSO, δ): 9.77 (1H, d, J=9 Hz), 9.36 (1H, s), 6.54 (2H, s), 5.87 (1H,dd, J=5, 9 Hz), 5.16 (1H, d, J=5 Hz), 4.74 (2H, AB_(q), J=13 Hz), 3.96(3H, s), 3.51 (2H, broad s).

(15)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer)

I.R. spectrum (Nujol): 3300, 1780, 1730, 1680, 1630 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm 9.89 (1H, d, J=8 Hz), 9.40 (1H, s),5.88 (1H, dd, J=5, 8 Hz), 5.20 (1H, d, J=5 Hz), 4.33 (2H, broad s), 4.01(3H, s), 3.93 (3H, s), 3.73 (2H, broad s).

(16)7-[2-Methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetamido]-3-[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

I.R. spectrum (Nujol): 1775, 1670, 1605 cm⁻¹.

N.M.R. spectrum (d₆ -DMSO, δ) ppm: 9.85 (1H, d, J=8 Hz), 9.43 (1H, s),5.83 (1H, dd, J=5, 8 Hz), 5.15 (1H, d, J=5 Hz), 4.37 (2H, t, J=5 Hz),4.30 (2H, broad s), 3.98 (3H, s), 3.65 (2H, broad s), 3.05 (2H, t, J=5Hz), 2.38 (6H, s).

EXAMPLE 20 (a) Preparation of the Starting Compound

(1) Ethyl 2-methoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer)(11.5 g) was added at 65° C. to a solution of tert-butyl nitrite (7.7 g)in dimethyl-formamide (30 ml) and the mixture was stirred for 30 minutesat the same temperature. The reaction mixture was poured into water (150ml) and the resultant mixture was extracted with ethyl acetate (100 ml).The extract was washed with a saturated aqueous solution of sodiumchloride, dried over magnesium sulfate and evaporated under reducedpressure. The residue was purified by column chromatography on silicagel to give ethyl 2-methoxyimino-2-(4-thiazolyl)acetate(syn isomer) (1.3g).

IR (film): 1730, 1600, 1500 cm⁻¹.

NMR (CDCl₃, δ): 1.4 (3H, t, J=7 Hz), 4.17 (3H, s), 4.48 (2H, q, J=7 Hz),7.75 (1H, d, J=2 Hz), 8.92 (1H, d, J=2 Hz).

(2) An 1N aqueous solution of sodium hydroxide (9.1 ml) was added to asolution of ethyl 2-methoxyimino-2-(4-thiazolyl)acetate(syn isomer)(1.3g) in methanol (15 ml) at ambient temperature and the mixture wasstirred for 3.5 hours at ambient temperature. The reaction mixture wasevaporated and the residue was dissolved in a saturated aqueous solutionof sodium bicarbonate (10 ml). The solution was washed with ethylacetate (15 ml) and acidified to pH 3.5 with 10% hydrochloric acid togive precipitates, which were collected by filtration to give colorlesspowder of 2-methoxyimino-2-(4-thiazolyl)acetic acid (syn isomer) (0.6g).

IR (Nujol): 1730, 1600, 1550 cm⁻¹

NMR (d₆ -DMSO, δ): 3.97 (3H, s), 8.08 (1H, d, J=2 Hz), 9.22 (1H, d, J=2Hz).

(b) Preparation of the Object Compound

To dimethylformamide (0.2 g) was added dropwise phosphorus oxychloride(0.4 g) under stirring and ice-cooling, and the mixture was stirred for30 minutes at 40° C. and then suspended in ethyl acetate (10 ml). To thesuspension was added 2-methoxyimino-2-(4-thiazolyl)acetic acid (synisomer) (0.4 g) under stirring and ice-cooling and then stirred for 30minutes under ice-cooling. Thus obtained solution was added to asolution, which was prepared by stirring a mixture of7-amino-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (0.76 g) and trimethylsilylacetamide (2.3 g) in ethyl acetate (20ml), under cooling to -25° C. The mixture was stirred for 1 hour at -20°C. to -10° C., and a saturated aqueous solution of sodium chloride (100ml) was added thereto. Thus obtained mixture was adjusted to pH 7.5 with20% aqueous solution of sodium carbonate, and the aqueous layer wasseparated. To the aqueous layer was added ethyl acetate, and adjusted topH 2 with 10% hydrochloric acid, and then extracted with ethyl acetate.The ethyl acetate layer was washed with a saturated aqueous solution ofsodium chloride, dried over magnesium sulfate and then evaporated. Theresidue was pulverized in diethyl ether, collected by filtration andthen dried to give7-[2-methoxyimino-2-(4-thiazolyl)-acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer) (1.01 g).

IR (Nujol): 3150, 1780, 1720, 1680, 1550 cm⁻¹.

NMR (d₆ -DMSO, δ): 3.67 (2H, broad s), 3.87 (3H, s), 4.32 (2H, AB_(q),J=13 Hz), 4.77-5.50 (5H, m), 5.57-6.17 (1H, m), 5.83 (1H, dd, J=5 and 8Hz), 7.88 (1H, d, J=2 Hz), 9.12 (1H, d, J=2 Hz), 9.62 (1H, d, J=8 Hz).

The following compounds were obtained according to similar manners tothose of the aforesaid examples.

(1) 7-[2-Methoxyimino-2-(4-thiazolyl)acetamido]cephalosporanic acid (synisomer).

IR (Nujol): 1775, 1715, 1670 cm⁻¹.

NMR (d₆ -DMSO, δ): 2.04 (3H, s), 3.58 (2H, m), 3.94 (3H, s), 4.88 (2H,ABq, J=12 Hz), 5.20 (1H, d, J=5 Hz), 5.87 (1H, dd, J=5 and 8 Hz), 7.97(1H, d, J=2 Hz), 9.19 (1H, d, J=8 Hz).

(2)7-[2-Methoxyimino-2-(4-thiazolyl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylicacid (syn isomer).

IR (Nujol): 3150, 1780, 1670, 1550 cm⁻¹.

NMR (d₆ -DMSO, δ): 3.73 (2H, broad s), 3.93 (3H, s), 4.47 (2H, ABq, J=13Hz), 5.17 (1H, d, J=5 Hz), 5.73 (1H, dd, J=5 and 8 Hz), 7.96 (1H, d, J=2Hz), 9.10 (1H, d, J=2 Hz), 9.57 (1H, s), 9.63 (1H, d, J=8 Hz).

What we claim is:
 1. The compounds of the formula: ##STR7## wherein R¹is 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl orisothiazol-4-yl, each of which may be substituted with lower alkyl, orthiazolyl;R^(2') is hydrogen, lower alkyl or a hydroxy protective group;and Z' is carboxy or protected carboxy, and soluble and non-toxic saltsthereof.
 2. The compounds of claim 1 whereinR¹ is 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl, R^(2') is lower alkyl, and Z'is carboxy.
 3. The compound of claim 2 which is2-methoxyimino-2-(1,2,3-thiadiazol-4-yl) acetic acid (syn isomer).